The present invention relates to a process for producing intermediates of quinolone antibacterial agents and aminoacrylic acid derivatives useful as intermediates of quinolone antibacterial agents.
Among quinolone compounds having a nitro group at the 5-position, a fluorine atom at the 6-position and a methyl group at the 8-position on the quinolone nucleus, the quinolone compound represented by the following formula 4 and the quinolone compound obtained from the quinolone compound represented by the formula 4 by reductive conversion of the nitro group at the 5-position to an amino group are known. These quinolone compounds are known to have strong antibacterial effect and be useful as synthetic antibacterial agents having reduced phototoxic, clastogenic and convulsive side effects (JP-A-8-198819, EP641793, Chem. Pharm. Bull., 44, 1074-1085(1996)). 
The quinolone intermediate (formula 8) as the starting material for the quinolone compound represented by the formula 4 can be synthesized by the route shown below, namely by reacting 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride with C2H5OMgCH(COOC2H5)2 to yield the compound (formula 5), hydrolyzing and decarboxlating the compound (formula 5) under heating to yield the compound (formula 6), reacting the compound (formula 6) with an alkyl orthoformate to yield a compound (formula 7: wherein R10 is an alkyl group)in the presence of acetic anhydride or propionic anhydride, reacting the compound (formula 7) with cyclopropylamine to yield the compound (formula 3A) and cyclizing the compound (formula 8) (JP-A-8-198819). 
However, the conventional process which requires a number of steps is not efficient and has a problem of low yield.
Further, there is another problem of the formation of the compound represented by the following formula 6A accompanying the formation of the compound (formula 6) which leads to the low yield. Still another problem is inapplicability of recrystallization to purification of the oily compounds (formula 6 and formula 6A). The high boiling points of the compound (formula 6) and the compound (formula 6A) which make it impossible to separate them by distillation are also problematic. For these reasons, in the conventional process, the compound (formula 6A) which remains intact after the formation of compound (formula 7) has been removed by column chromatography. 
The present invention provides a novel process for producing a highly pure intermediate of synthetic quinolone antibacterial agents through a small number of steps and a simple purification step which solves the above-mentioned problems. The present invention also provides a novel compound (formula 1) useful as an intermediate of quinolone compounds having an amino group or a nitro group at the 5-position, a fluorine atom at the 6-position and a methyl group at the 8-position on the quinolone nucleus. Namely, the present invention provides a process for producing a benzoylacrylic acid derivative represented by the following formula 3, which comprises reacting 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride with a compound represented by the following formula 2 to yield an aminoacrylic acid derivative represented by the following formula 1 and then reacting the aminoacrylic acid derivative represented by the formula 1 with an amine derivative represented by R2xe2x80x94NH2: wherein R is a lower alkyl group, R2 is an alkyl group, a cycloalkyl group, an aralky group, an allyl group, an aryl group, an amino group, an alkylamino group or a dialkylamino group. 
The present invention also provides an aminoacrylic acid derivative represented by formula 1.
The process of the present invention is represented by the following reaction scheme. 
In the process of the present invention, firstly, 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride is reacted with a compound (formula 2) to yield an aminoacrylic acid derivative (formula 1). This reaction step is referred to as reaction step-1 hereinafter.
R1 in formula 2 is a lower alkyl group, preferably a C1-4 linear alkyl group, especially preferably a methyl group or an ethyl group. Though the aminoacrylic acid derivative (formula 1) and the compound (formula 2) have cis-isomers and trans-isomers which have substituents at different positions in relation to the double bond, the cis-isomers are preferable in the present invention.
The compound (formula 2) is a known compound and readily obtainable by conventional production processes. Specific examples of the compound (formula 2) include methyl 3-dimethylaminoacrylate, ethyl 3-dimethylaminoacrylate, propyl 3-dimethylaminoacrylate and butyl 3-dimethylaminoacrylate.
In reaction step-1, the amount of the compound (formula 2) is from 0.5 to 10 times, preferably from 1 to 2 times, as many moles as the amount of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride.
It is preferred to carry out reaction step-1 in the presence of a base.
As the base, a tertiary organic amine represented by (R10) (R11) (R12)N (wherein each of R10, R11 and R12 which may be the same or different, is a C1-4 alkyl group or a benzyl group), ammonia, pyridine or a cyclic amine shown below (wherein R13, R14 R15 and R16 are independently C1-4 alkyl groups or benzyl groups) is preferred. 
As the base, pyridine is particularly preferred. Use of pyridine as the base reduces production of the by-product and has the advantage of considerable increase in yield.
The amount of the base is from 0.5 to 3 times, preferably from 1 to 2 times, as many moles as the amount of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride.
It is preferred to carry out reaction step-1 in the presence of a reaction solvent. As the reaction solvent, ethyl acetate, acetonitrile, toluene, xylene, a hydrocarbon solvent, N,N-dimethylformamide or dimethyl sulfoxide may be mentioned. The amount of the reaction solvent is from 1 to 100 times as much by weight as the amount of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride.
The reaction temperature for reaction step-1 is preferably from 0xc2x0 C. to 25xc2x0 C., and the reaction time is preferably from 0.5 to 24 hours. The aminoacrylic acid derivative (formula 1) obtained by this reaction is a novel compound. R1 in formula 1 corresponds to R1 in formula 2 and is the same as defined in formula 2. Specific examples of the aminoacrylic acid derivative (formula 1) include the following compounds:
methyl 3-dimethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-dimethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-dimethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate, and
butyl 3-dimethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate.
In the present invention, though the crude reaction product obtained in reaction step-1 may be directly used for reaction step-2 described below, it is preferably subjected to ordinary post-treatment. Especially, when reaction step-1 is carried out in the presence of a base, post-treatment for removal of the resulting salt of the base with hydrochloric acid is preferably carried out before reaction step-2. Because the reaction in reaction step-1 is highly selective and gives a high conversion degree enough to necessitate no special separation operation in the post-treatment, filtration is preferable. The salt of the base with hydrochloric acid is removed sufficiently by filtration. In the present invention, next, the aminoacrylic acid derivative (formula 1) is reacted with an amine derivative represented by R2xe2x80x94NH2 to yield a benzoylacrylic acid derivative (formula 3). This reaction step is referred to as reaction step-2 hereinafter.
R2 in the amine derivative represented by R2xe2x80x94NH2 is an alkyl group, a cycloalkyl group, an aralky group, an allyl group, an aryl group, an amino group, a monoalkylamino group or a dialkylamino group. Specific examples of these groups are those shown in the benzoylacrylic acid derivative (formula 3).
As the amine derivative represented by R2xe2x80x94NH2, cyclopropylamine having a cyclopropyl group as R2 is preferable. The amount of the amine derivative represented by R2xe2x80x94NH2 is from 0.5 to 10 times, preferably from 1 to 2 times, as many moles as the amount of the aminoacrylic acid derivative (formula 1).
Examples of the benzoylacrylic acid derivative (formula 3) include the following compounds.
Examples of the benzoylacrylic acid derivative (formula 3) wherein R2 is an alkyl group:
methyl 3-methylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-methylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-methylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-methylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-ethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-ethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-ethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-ethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-propylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-propylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-propylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-propylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-butylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-butylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-butylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate, and
butyl 3-butylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate.
Examples of the benzoylacrylic acid derivative (formula 3) wherein R2 is a cycloalkyl group:
methyl 3-cyclopropylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-cyclopropylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-cyclopropylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-cyclopropylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-cyclobutylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-cyclobutylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-cyclobutylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-cyclobutylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-cyclopentylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-cyclopentylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-cyclopentylamino-2-(2,4,5-trifluoro-3-ethyl-6-nitrobenzoyl)acrylate,
butyl 3-cyclopentylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-cyclohexylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-cyclohexylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-cyclohexylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate, and
butyl 3-cyclohexylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate.
Examples of the benzoylacrylic acid derivative (formula 3) wherein R2 is an aralkyl group:
methyl 3-benzylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-benzylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-benzylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate, and
butyl 3-benzylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate.
Examples of the benzoylacrylic acid derivative (formula 3) wherein R2 is an allyl group:
methyl 3-allylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-allylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-allylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate, and
butyl 3-allylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate.
Examples of the benzoylacrylic acid derivative (formula 3) wherein R2 is an aryl group:
methyl 3-anilino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-anilino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-anilino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate, and
butyl 3-anilino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate.
Examples of the benzoylacrylic acid derivative (formula 3) wherein R2 is an alkylamino group:
methyl 3-(Nxe2x80x2-methylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-(Nxe2x80x2-methylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-(Nxe2x80x2-methylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-(Nxe2x80x2-methylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-(Nxe2x80x2-ethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-(Nxe2x80x2-ethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-(Nxe2x80x2-ethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-(Nxe2x80x2-ethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-(Nxe2x80x2-propylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-(Nxe2x80x2-propylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-(Nxe2x80x2-propylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-(Nxe2x80x2-propylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-(Nxe2x80x2-butylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-(Nxe2x80x2-butylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-(Nxe2x80x2-butylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-(Nxe2x80x2-butylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-(Nxe2x80x2-tert-butylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-(Nxe2x80x2-tert-butylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-(Nxe2x80x2-tert-butylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate, and
butyl 3-(Nxe2x80x2-tert-butylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate.
Examples of the benzoylacrylic acid derivative (formula 3) wherein R2 is a dialkylamino group:
methyl 3-(Nxe2x80x2,Nxe2x80x2-dimethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-(Nxe2x80x2,Nxe2x80x2-dimethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-(Nxe2x80x2,Nxe2x80x2-dimethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-(Nxe2x80x2,Nxe2x80x2-dimethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-(Nxe2x80x2,Nxe2x80x2-diethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-(Nxe2x80x2,Nxe2x80x2-diethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-(Nxe2x80x2,Nxe2x80x2-diethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-(Nxe2x80x2,Nxe2x80x2-diethylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-(Nxe2x80x2,Nxe2x80x2-dipropylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-(Nxe2x80x2,Nxe2x80x2-dipropylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-(Nxe2x80x2,Nxe2x80x2-dipropylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
butyl 3-(Nxe2x80x2,Nxe2x80x2-dipropylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
methyl 3-(Nxe2x80x2,Nxe2x80x2-dibutylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
ethyl 3-(Nxe2x80x2,Nxe2x80x2-dibutylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate,
propyl 3-(Nxe2x80x2,Nxe2x80x2-dibutylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate, and
butyl 3-(Nxe2x80x2,Nxe2x80x2-dibutylhydrazino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate.
The reaction temperature for reaction step-2 is preferably lower than 10xc2x0 C. A temperature which is xe2x88x9210xc2x0 C. or above and is lower than +10xc2x0 C., particularly from 0 to 5xc2x0 C., is particularly preferred. A reaction temperature of 10xc2x0 C. or above unfavorably increases the by-product and thereby decreases the yield. It is preferred to keep the reaction product lower than 10xc2x0 C., because heating after completion of the reaction can lead to increase of the by-product.
It is preferred to carry out reaction step-2 in the presence of a reaction solvent. As the reaction solvent, a reaction solvent which allows precipitation of the benzoylacrylic acid derivative (formula 3) or a reaction solvent which allows precipitation of the benzoylacrylic acid derivative (formula 3) on addition of water after completion of the reaction is preferred. As the reaction solvent, methanol or ethanol may be mentioned. The amount of the reaction solvent is preferably from 0.5 to 100 times as much by weight as the amount of the aminoacrylic acid derivative (formula 1).
Further, it is preferred to carry out the reaction in the absence of an acid. The reaction can give a high yield of a compound represented by formula 3 even in the absence of an acid.
The bonzoylacrylic acid derivative (formula 3) is useful as an intermediate for production of quinolone compounds having an amino group or a nitro group at the 5-position, a fluorine atom at the 6-position and a methyl group at the 8-position on the quinolone nucleus and convertible to the quinolone compound represented by the previously mentioned formula 4 which is useful as a synthetic antibacterial agent by the process disclosed in JP-A-8-198819.
Now, the present invention will be described by referring to Examples. However, the present invention is by no means restricted to such specific Examples. High performance liquid chromatography (HPLC) was done under the following conditions.
Detector: UV (240 nm)
Column: TSK-gel ODS-80TM
Column Temp.: 30xc2x0 C.
Mobile phase: (acetonitrile)/(pH 7.0 phosphate buffer)=1/1
Flow rate: 1.0 ml/min